RESEARCH PROJECT The evidence-based treatments for cLBP typically include a combination of pharmacologic, non-pharmacologic and procedural treatments. However, none of these treatments works well in more than a fraction of patients, and at present there is little guidance regarding what treatment should be used in which patients (i.e. precision medicine). The BACPAC precision medicine initiative for cLBP will attempt to solve this problem by deeply phenotyping cLBP participants to identify the various underlying mechanisms causing cLBP. We feel that a critical element of such phenotyping is to also understand which participants respond to which therapies, so that we can then eventually choose the appropriate treatment for a cLBP patient based on which underlying mechanisms are contributing to their pain and dysfunction. Our central hypothesis in our BACPAC MRC Research Project is that an Interventional Response Phenotyping study can identify individuals with different underlying mechanisms for their pain who thus respond differentially to evidence-based interventions for cLBP?. To address this hypothesis, we will conduct a randomized controlled SMART study of cLBP with the following three aims. The first aim is to perform an Interventional Response Phenotyping study in a cohort of cLBP patients. We will perform a pragmatic trial using a cohort of cLBP patients (n=500), who will receive a sequence of interventions known to be effective in cLBP. For 6 weeks, all cLBP participants will receive a web- based self-management program for pain. After six weeks, individuals who remain symptomatic will be enrolled in a Sequential, Multiple Assessment, Randomized Trial (SMART) design study and randomized to a series of treatments, including: a) mindfulness based cognitive therapy, b) physical therapy/exercise, c) acupressure, d) duloxetine, or e) pregabalin. After 12 weeks, individuals who remain symptomatic will be re-randomized to a different treatment for an additional 12 weeks. Having this information on all participants, we will overlay Aims 2 and 3, which will identify the subsets of participants that respond to each treatment. In Aim 2, we will show that currently available, clinically-derived measures, can predict differential responsiveness to the above therapies. In Aim 3, a subset of the individuals in Aims 1 and 2 will receive deeper phenotyping (n=200), to identify new experimental measures that predict differential responsiveness to each of the above therapies, as well as to infer mechanisms of action of treatments. These deep phenotyping visits take nearly an entire day each, will be performed prior to each treatment period and at the completion of the study, and will include functional neuroimaging, quantitative sensory testing, plasma measures of inflammation, and measures of autonomic tone.